Molecular and cellular mechanisms of tight junction dysfunction in the irritable bowel syndrome

Peng, Cheng; Yao, Jianning; Wang, Chunfeng; Zhang, Lianfeng; Kong, Wei

doi:10.3892/mmr.2015.3808

Cited by 40 publications

(38 citation statements)

References 28 publications

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“…21 Clinical colonoscopy biopsies harvested from diarrhoeapredominant IBS (IBS-D) patients demonstrated decreased CLDN1 levels, while CLDN1 was increased in constipation-predominant IBS (IBS-C) patients. 22 The CLDN1 promoter is under the dual reciprocal regulation by HES1 and NR3C1 in Caco-2 cells and a validated chronic, intermittent water avoidance (WA) stress rat model of stress-induced enhanced abdominal pain that mimics several clinical features observed in IBS-D patients. 12 We observed down-regulation of both HES1 and NR3C1 via a glucocorticoid negative feedback pathway in WA-stressed rat colon crypts, and similar trends were observed in the hippocampus in a validated restraint-stress mouse model demonstrating anxiety and depression-like behaviours.…”

Section: Functional Bowel Disorders (Fbd) and Colorectal Cancersupporting

confidence: 73%

“…Functional bowel disorders including irritable bowel syndrome (IBS) represent dysfunction in the bidirectional brain‐gut axis, intestinal barrier integrity and interactions with the microbiota and dietary factors . Clinical colonoscopy biopsies harvested from diarrhoea‐predominant IBS (IBS‐D) patients demonstrated decreased CLDN1 levels, while CLDN1 was increased in constipation‐predominant IBS (IBS‐C) patients . The CLDN1 promoter is under the dual reciprocal regulation by HES1 and NR3C1 in Caco‐2 cells and a validated chronic, intermittent water avoidance (WA) stress rat model of stress‐induced enhanced abdominal pain that mimics several clinical features observed in IBS‐D patients .…”

Section: Some Potential Applications Of Turing Pattern Analysis In Gasupporting

confidence: 58%

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Hypothesis: Caco‐2 cell rotational 3D mechanogenomic turing patterns have clinical implications to colon crypts

Zheng

Kalinin

Dinov

et al. 2018

J Cellular Molecular Medi

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Colon crypts are recognized as a mechanical and biochemical Turing patterning model. Colon epithelial Caco‐2 cell monolayer demonstrated 2D Turing patterns via force analysis of apical tight junction live cell imaging which illuminated actomyosin meshwork linking the actomyosin network of individual cells. Actomyosin forces act in a mechanobiological manner that alters cell/nucleus/tissue morphology. We observed the rotational motion of the nucleus in Caco‐2 cells that appears to be driven by actomyosin during the formation of a differentiated confluent epithelium. Single‐ to multi‐cell ring/torus‐shaped genomes were observed prior to complex fractal Turing patterns extending from a rotating torus centre in a spiral pattern consistent with a gene morphogen motif. These features may contribute to the well‐described differentiation from stem cells at the crypt base to the luminal colon epithelium along the crypt axis. This observation may be useful to study the role of mechanogenomic processes and the underlying molecular mechanisms as determinants of cellular and tissue architecture in space and time, which is the focal point of the 4D nucleome initiative. Mathematical and bioengineer modelling of gene circuits and cell shapes may provide a powerful algorithm that will contribute to future precision medicine relevant to a number of common medical disorders.

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Section: Functional Bowel Disorders (Fbd) and Colorectal Cancersupporting

confidence: 73%

Section: Some Potential Applications Of Turing Pattern Analysis In Gasupporting

confidence: 58%

Hypothesis: Caco‐2 cell rotational 3D mechanogenomic turing patterns have clinical implications to colon crypts

Zheng

Kalinin

Dinov

et al. 2018

J Cellular Molecular Medi

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“…However, neither expression nor distribution of occludin or claudin-1 proteins were analyzed in response to GCD or GFD challenge 18 . Further, other studies have described increased claudin-1 expression in IBS with constipation (IBS-C) 52 , which we have recently found to lack changes in paracellular permeability (manuscript in preparation, Grover, M. et al). Thus, even though mucosal claudin-1 expression is likely reduced in IBS-D patients relative to healthy controls as well as following challenge with GCD, relative to challenge with GFD, the impact on paracellular permeability remains unknown.…”

Section: Discussionsupporting

confidence: 50%

Gluten-induced symptoms in diarrhea-predominant irritable bowel syndrome are associated with increased myosin light chain kinase activity and claudin-15 expression

Vázquez-Roque

Carlson

et al. 2017

Laboratory Investigation

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The mechanisms underlying diarrhea-predominant irritable bowel syndrome (IBS-D) are poorly understood, but increased intestinal permeability is thought to contribute to symptoms. A recent clinical trial of gluten-free diet (GFD) demonstrated symptomatic improvement, relative to gluten-containing diet (GCD), that was associated with reduced intestinal permeability in non-celiac disease IBS-D patients. The aim of this study was to characterize intestinal epithelial tight junction composition in IBS-D before and after dietary gluten challenge. Biopsies from 27 IBS-D patients (13 GFD; 14 GCD) were examined by H&E staining and semi-quantitative immunohistochemistry for phosphorylated myosin II regulatory light chain (MLC), MLC kinase, claudin-2, claudin-8, and claudin-15. Diet-induced changes were assessed and correlated with urinary mannitol excretion (after oral administration). In the small intestine, epithelial MLC phosphorylation was increased or decreased by GCD or GFD, respectively, and this correlated with increased intestinal permeability (P < 0.03). Colonocyte expression of the paracellular Na+ channel claudin-15 was also markedly augmented following GCD challenge (P < 0.05). Conversely, colonic claudin-2 expression correlated with reduced intestinal permeability (P < 0.03). Claudin-8 expression was not affected by dietary challenge. These data show that alterations in MLC phosphorylation and claudin-15 and claudin-2 expression are associated with gluten-induced symptomatology and intestinal permeability changes in IBS-D. The results provide new insight into IBS-D mechanisms and can explain permeability responses to gluten challenge in these patients.

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“…32,36 Reduced tight junction expression of claudin-1 (called the sealing claudin) in mucosa from human ileum and ascending colon have been reported in patients with IBS-D (and conversely, levels of claudin-1 are increased in patients with constipation). 37 Tight junction dysfunction also appears to contribute to development of diarrhea following infection with Giardia lamblia , as well as post-infectious sequelae, at least in an animal model. 38 However, measurement of intestinal permeability 39,40 in patients with chronic diarrhea should be considered as only a research tool, rather than for use in the clinic.…”

Section: Intestinal Barrier Functionmentioning

confidence: 99%

Pathophysiology, Evaluation, and Management of Chronic Watery Diarrhea

2017

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Chronic watery diarrhea poses a diagnostic and therapeutic challenge and is often a disabling condition for patients. Although acute diarrhea is likely to be caused by infection, the causes of chronic diarrhea (more than 4 weeks in duration) are more elusive. We review on the pathophysiology, diagnosis, and treatment of chronic diarrhea. Drawing on recent insights into the molecular mechanisms of intestinal epithelial transport and barrier function, we discuss how diarrhea can result from a decrease in luminal solute absorption, an increase in secretion, or both, as well as derangements in barrier properties. We also describe the various extra-epithelial factors that activate diarrheal mechanisms. Finally, clinical evaluation and tests used in assessment of patients presenting with chronic diarrhea are reviewed, and an algorithm guiding therapeutic decisions and pharmacotherapy is presented.

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Molecular and cellular mechanisms of tight junction dysfunction in the irritable bowel syndrome

Cited by 40 publications

References 28 publications

Hypothesis: Caco‐2 cell rotational 3D mechanogenomic turing patterns have clinical implications to colon crypts

Hypothesis: Caco‐2 cell rotational 3D mechanogenomic turing patterns have clinical implications to colon crypts

Gluten-induced symptoms in diarrhea-predominant irritable bowel syndrome are associated with increased myosin light chain kinase activity and claudin-15 expression

Pathophysiology, Evaluation, and Management of Chronic Watery Diarrhea

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